IFN-gamma-inducing factor/IL-18 administration mediates IFN-gamma- and IL-12-independent antitumor effects.
We evaluated the mechanism of the antitumor effects of mouse rIFN-gamma-inducing factor/IL-18 protein on the growth of mouse tumor cell lines in vivo. Mice received IL-18 before or after challenge with CL8-1, a mouse melanoma cell line. Both regimens significantly suppressed tumor growth and reduced the number of mice with growth of tumor from 60% (3/5) to 20% (1/5). Furthermore, IL-18 administered before and after tumor inoculation completely abrogated the establishment of CL8-1 in all animals. IL-18 administration also significantly suppressed the growth of MCA205, a sarcoma cell line, even when treatment was delayed to 7 days following tumor inoculation. Although IL-18/IL-12 combination therapy had the most significant and immediate antitumor effects, many mice so treated succumbed with markedly elevated serum IFN-gamma levels. The antitumor effects of IL-18 were abrogated almost completely when NK cells were eliminated using anti-asialo GM1 Ab administration, but only marginally impaired in IFN-gamma or IL-12 gene-disrupted mice. Immunohistochemical staining revealed that the number of the CD8+ T cells, but not CD4+ T cells, found at the tumor site was reduced in animals treated with IL-18. These results indicate that IL-18 has potent antitumor effects mediated by CD4+ T cells and NK cells, but in IFN-gamma- and IL-12-independent pathways.
Osaki
T
T
Department of Surgery, University of Pittsburgh School of Medicine, PA 15213, USA.
Péron
J M
JM
Cai
Q
Q
Okamura
H
H
Robbins
P D
PD
Kurimoto
M
M
Lotze
M T
MT
Tahara
H
H
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D016516:CD4-CD8 Ratio / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D016207:Cytokines / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D003602:Cytotoxicity, Immunologic; D005354:Fibrosarcoma / Q000276:immunology / Q000517:prevention & control; D005677:G(M1) Ganglioside / Q000276:immunology; D017353:Gene Deletion; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D007106:Immune Sera / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007369:Interferon Inducers / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics / Q000502:physiology*; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D020382:Interleukin-18; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000276:immunology / Q000517:prevention & control; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D016207:Cytokines; D006131:Growth Inhibitors; D007106:Immune Sera; D007369:Interferon Inducers; D020382:Interleukin-18; D016753:Interleukin-10; D018664:Interleukin-12; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; D007371:Interferon-gamma